Lysyl-tRNA synthetase 1 promotes atherogenesis via autophagy-related secretion and inflammation.

Lysyl-tRNA synthetase 1 (KARS1), an aminoacyl-tRNA synthetase, was recently identified as a secreted pro-inflammatory agent. However, the vascular secretion and functions of KARS1 have not been characterized. This study investigated the secretion mechanisms of KARS1 and explored its functional roles in vascular biology. We found that KARS1 expression was upregulated by oscillatory shear stress, an atherogenic factor, suggesting the presence of free KARS1 dissociated from aminoacyl-tRNA synthetase complexes. Moreover, in the presence of Ca, serum starvation triggered free cytosolic KARS1 release from endothelial cells via secretory autophagy. Both phosphatidylinositol 3-phosphate kinase and caveolin-1 were either supplementary or essential for KARS1 secretion. Secreted KARS1 co-localized in the exosome fraction of post-culture media and was externally exposed. Further, secreted KARS1 inhibited shear-induced activation of various signaling molecules, including extracellular signal-regulated kinase, protein kinase B, and endothelial nitric oxide synthetase. Secreted KARS1 in atherosclerotic plaques also acted as an atherogenic or proinflammatory autocrine/paracrine molecule. Additionally, KARS1 participated in vessel alteration. Collectively, these findings describe novel vascular features of KARS1 in response to shear stress, providing insights into shear stress-controlling mechanisms of the vascular system.